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1.
Embase;
Preprint in English | EMBASE | ID: ppcovidwho-326972

ABSTRACT

The mutational landscape of SARS-CoV-2 varies at both the dominant viral genome sequence and minor genomic variant population. An early change associated with transmissibility was the D614G substitution in the spike protein. This appeared to be accompanied by a P323L substitution in the viral polymerase (NSP12), but this latter change was not under strong selective pressure. Investigation of P323L/D614G changes in the human population showed rapid emergence during the containment phase and early surge phase of wave 1 in the UK. This rapid substitution was from minor genomic variants to become part of the dominant viral genome sequence. A rapid emergence of 323L but not 614G was observed in a non-human primate model of COVID-19 using a starting virus with P323 and D614 in the dominant genome sequence and 323L and 614G in the minor variant population. In cell culture, a recombinant virus with 323L in NSP12 had a larger plaque size than the same recombinant virus with P323. These data suggest that it may be possible to predict the emergence of a new variant based on tracking the distribution and frequency of minor variant genomes at a population level, rather than just focusing on providing information on the dominant viral genome sequence e.g., consensus level reporting. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions.

2.
European Heart Journal ; 42(SUPPL 1):3383, 2021.
Article in English | EMBASE | ID: covidwho-1553901

ABSTRACT

Background: Human cardiac pericytes (PC) were proposed as the main cellular target for SARS-CoV-2 in the heart due to high transcriptional levels of the angiotensin-converting enzyme 2 (ACE2) receptor. Emerging reports indicate CD147/Basigin (BSG), highly expressed in endothelial cells (EC), is an alternative SARS-CoV-2 receptor. To date, the mechanism by which the virus infects and disrupts the heart vascular cells was not identified yet. Moreover, cleaved Spike (S) protein molecules could be released into the bloodstream from the leaking pulmonary epithelial-endothelial barrier in patients with severe COVID-19, opening to the possibility of non-infective diseases in organs distant from the primary site of infection. Purposes: (1) to confirm that human primary cardiac PC express ACE2 and CD147;(2) to verify if PC are permissible to SARS-CoV-2 infection;(3) to investigate if the recombinant SARS-CoV-2 S protein alone, without the other viral elements, can trigger molecular signalling and induce functional alterations in PC;(4) to explore which viral receptor is responsible for the observed events. Methods and results: Cardiac PC express both the ACE2 and CD147 receptors at mRNA and protein level. Incubation of PC for up to 5 days with SARS-CoV-2 expressing the green fluorescent protein (GFP) did not show any evidence of cell infection or viral replication. Next, we exposed the PC to the recombinant S protein (5.8 nM) and confirmed that the protein engaged with cellular receptors (western blot analysis of S protein in treated and control PC). Incubation with the S protein increased PC migration (wound closure assay, P<0.01 vs ctrl) and reduced the formation of tubular structures between PC and EC in a Matrigel assay (P<0.01 vs ctrl). Moreover, the S protein promoted the production of pro-inflammatory factors typical of the cytokine storm in PC (ELISA measurement of MCP1, IL-6, IL-1β, TNFα, P<0.05 vs ctrl), and induced the secretion of proapoptotic factors responsible for EC death (Caspase 3/7 assay, P<0.05 vs ctrl). Signalling studies revealed that the S protein triggers the phosphorylation/ activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in cardiac PC. The neutralization of CD147, using a blocking antibody, prevented ERK1/2 activation in PC, and was reflected into a partial rescue of the cell functional behaviour (migration and pro-angiogenic capacity). In contrast, blockage of CD147 failed to prevent the pro-inflammatory response in PC. Conclusions: We propose the novel hypothesis that COVID-19 associated heart's microvascular dysfunction is prompted by circulating S protein molecules rather than by the direct coronavirus infection of PC. Besides, we propose CD147, and not ACE2, as the leading receptor mediating S protein signalling in cardiac PC.

3.
Chest ; 160(4):A278, 2021.
Article in English | EMBASE | ID: covidwho-1458186

ABSTRACT

TOPIC: Chest Infections TYPE: Fellow Case Reports INTRODUCTION: Strongyloides stercoralis is a parasitic infection that is endemic in subtropical and tropical climates. Due to the unique life cycle of this parasite, many hosts are asymptomatic. If a host becomes immunosuppressed, a hyperinfection syndrome caused by proliferation of these nematodes can ensue (1). CASE PRESENTATION: A 72-year-old Nicaraguan male was admitted to the hospital with dyspnea. A nasopharyngeal swab confirmed SARS-COV2 infection. He was admitted to the medical floor but was transferred to the intensive care unit due to worsening hypoxia. He was subsequently intubated and treated with intravenous dexamethasone and full dose anticoagulation. His course was complicated by acute respiratory distress syndrome ultimately necessitating tracheostomy, multi-drug resistant Escherichia coli pneumonia, prolonged shock requiring continuous vasopressor support and stress dose steroids, diarrhea, and persistent fevers despite broad antimicrobial coverage. His peripheral eosinophil count was noted to be elevated. This in combination with his Nicaraguan origin prompted a stool ova and parasite examination to evaluate for helminthic infection. Microscopic evaluation revealed rhabditiform larvae consistent with Strongyloides stercoralis. Review of a bronchoalveolar lavage gram stain demonstrated a larvae-like structure suspicious for Strongyloides stercoralis as well. He was diagnosed with disseminated strongyloidiasis and treated with ivermectin. His fevers and vasopressor requirements subsequently resolved. DISCUSSION: High dose glucocorticoid therapy has a known immunosuppressive effect on a host's response to infectious agents. In this case, the use of steroids for COVID-19 and shock resulted in strongyloides hyperinfection syndrome. The presence of an Escherichia coli pneumonia was, in retrospect, an important clue to the patient's presentation. Bacterial pneumonia from enteric organisms has been found to be a common co-infection in patients with pulmonary strongyloidiasis (2). Bacteria are transmitted from the intestine, where the larvae start their life cycle. They move into the bloodstream via penetration of the intestinal mucosa by the larvae. The larvae then carry the bacteria into the lungs by burrowing into the alveoli (2). Strongyloides is estimated to infect millions of people worldwide and thus there appears to be an increased risk for associated hyperinfection in the setting of steroid utilization for COVID-19 infections (3). It is important for clinicians to be aware of this risk and to delineate strategies for appropriate testing and initiation of treatment. CONCLUSIONS: Disseminated strongyloidiasis can be detrimental in patients with COVID-19. In the setting of a global pandemic during which one of the mainstays of treatment is high dose glucocorticoids, it is important to be cognizant of dormant infections like Strongyloides that may become unmasked during treatment. REFERENCE #1: Nutman TB. Human infection with Strongyloides stercoralis and other related Strongyloides species. Parasitology. 2017 Mar;144(3):263-273. REFERENCE #2: Nabeya, D., Haranaga, S., Parrott, G.L. et al. Pulmonary strongyloidiasis: assessment between manifestation and radiological findings in 16 severe strongyloidiasis cases. BMC Infect Dis 17, 320 (2017). REFERENCE #3: Stauffer WM, Alpern JD, Walker PF. COVID-19 and Dexamethasone: A Potential Strategy to Avoid Steroid-Related Strongyloides Hyperinfection. JAMA. 2020;324(7):623–624. DISCLOSURES: No relevant relationships by William Bender, source=Web Response No relevant relationships by Eliana Gonzalez, source=Web Response No relevant relationships by Anjali Patel, source=Web Response No relevant relationships by Margaret Williamson, source=Web Response

6.
Journal of Cystic Fibrosis ; 20:S51, 2021.
Article in English | EMBASE | ID: covidwho-1368824

ABSTRACT

Background: Real-world, post-approval studies contribute significantly to the evidence surrounding the impact of new treatments, including CFTR modulators, but can be complex undertakings. Elexacaftor-tezacaftor-ivacaftor (ETI) was approved by EMA sooner than expected in August 2020 during a global pandemic. Method: RECOVER, a multi-centre, post-approval study examining the impact of ETI, and conducted in 8 clinical sites in Ireland and the UK over 2 years, examines important outcomes in children and adults prescribed ETI. The study will be conducted in 2 phases in line with ETI approval: 12+ and 6–11. In addition to routine data collected as part of normal care, key RECOVER endpoints include lung clearance index (LCI), spirometry-controlled CT, treatment adherence, GI symptoms, inflammation, liver disease markers, nasal inflammation and nitric oxide metabolism. Results: To date, 96 participants (56% female) out of a target of 137 in people with CFaged 12 and above, have been recruited (predominantly 12–18yrs to date). Recruitment and sample collection has been impacted by the effect of COVID-19 on CF care and CF centre attendance. Key challenges have included: Sputum collection (risks of induction and non-sputum producing participants) and coordination of study activities with limited clinic attendance. Despite this, key baseline data, prior to commencing treatment, has been successfully collected on the majority of participants to date. For subjects recruited to date, 56% have F508del/F508del and 44% F508del/minimum function mutations, mean age is 16.1 years, mean FEV1 83.6% (23–111%), mean LCI 12.2 (6.9–24.3). Recruitment and data collection is ongoing. Conclusion: Despite the impact of accelerated approval and COVID-19, we have been able to proceed with study initiation, recruitment and sample collection. Data from RECOVER and other international post-approval studies is likely to add significantly to our understanding of the impact of ETI on people with CF.

7.
Topics in Antiviral Medicine ; 29(1):41, 2021.
Article in English | EMBASE | ID: covidwho-1250394

ABSTRACT

Background: Clinical outcomes for people living with HIV (PLWH) hospitalized with COVID-19 infections have shown mixed outcomes. We conducted a multicentre, UK retrospective matched cohorts' analysis. Methods: Index cases were HIV+ COVID-19 PCR+ patients hospitalized between dates 1st February - 31st May 2020. HIV-negative patients were matched to PLWH up to a 3:1 ratio across 6 sites in England, by hospital site, test date +/- 7 days, age +/- 5 years, gender, index of multiple deprivation decile (IMDD) +/- 1. The primary outcome was patients achieving ≥2-point improvement on a 7-point ordinal scale or discharge from hospital by day 28, whichever was earlier. Follow up was right-censored at day 28 for patients still in hospital. Baseline characteristics and outcomes were analysed by Coxproportional hazards regression stratified by matching clusters using multiple imputation for missing data. The model adjusted for ethnicity, clinical frailty score, body mass index, baseline hypoxia, duration of symptoms, hypertension, diabetes, malignancy, cardiac, lung and renal disease. Results: 68 PLWH and 181 HIV-negative patients were included. PLWH had an HR of 0.57 (95%CI 0.39, 0.85;p=0.005) of achieving 2-point improvement or discharge compared to HIV-negative patients. The effect size of HIV-status was attenuated (aHR 0.70;0.43, 1.17;P=0.18) after adjustment in the multivariable model (Table 1), with baseline frailty (aHR=0.79;95%CI 0.65, 0.95;p=0.011 ), malignancy (aHR=0.37;95%CI 0.17, 0.82;p=0.014) having a greater impact on the primary outcome. Proportion of deaths (19.1% vs 19.3%, p=0.266) and patients requiring ventilation (23.5% vs 17.1%, p=0.25) were similar between PLWH and HIV-negative patients. Sensitivity analyses adjusting for age and excluding missing data, remained consistent with main findings. PLWH were frailer (median clinical frailty score 3 vs 2, p=0.0069), and had higher proportion of malignancies (14.7% vs 9.9%, p=0.29) although not statistically significant. Number of non-HIV co-morbidities (2 vs 2, p=0.16) and median BMI (27.7 vs 29.4, p=0.19) were similar. The median CD4 count of PLWH was 352cells/ μL (IQR 235, 619), and 63/68 (92.3%) were taking antiretroviral therapy. Conclusion: Although PLWH were less likely to achieve improvement or discharge, after adjustment the effect of HIV-status was attenuated. Increased baseline frailty and active malignancies remain associated with poorer COVID-19 outcomes.

8.
Counselling Psychology Quarterly ; : No Pagination Specified, 2020.
Article | APA PsycInfo | ID: covidwho-828546

ABSTRACT

ABSTRACT In early 2020, the world was thrust into a crisis with the advent of the COVID-19 pandemic. This resulted in the sudden expansion of telepractice in the mental health field for licensed mental health providers and trainees. Prior to the pandemic, few mental health training programs provided training opportunities in telehealth service delivery. The [name removed for blind review] (TBC) is one of a few telemental health training programs in the world. The TBC has provided telehealth services to rural and underserved populations since 2009 with a hub and spoke model of care, but due to constraints related to the pandemic has recently transitioned to an all in-home model of telehealth service delivery. The present paper highlights recent policy changes to in-home telepractice and the TBC methodology for transitioning to in-home service delivery. Results include solutions to common pitfalls in areas such as communication and logistics, clinical supervision and consultation, and boundary setting. Recommendations are also provided for the development of training programs throughout the world to equip mental health trainees in telehealth service delivery. Mental health practitioners are poised to thrive in the face of adversity during the COVID-19 pandemic and trainees should not be left behind. (PsycInfo Database Record (c) 2020 APA, all rights reserved)

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